The number of obese individuals continues to increase worldwide, contributing to millions of deaths each year. Research investigating the neural underpinnings of overnutrition has traditionally focused on the hypothalamus, where metabolism is thought to be regulated. However, parts of the brain involved in decision making (prefrontal cortex) and reward processing (nucleus accumbens) are now hypothesized to play an important role in compulsive, or habitual, feeding. The goal of this proposal is to investigate how the prefrontal cortex and the nucleus accumbens may be working together to control food intake. We will use a novel, "optogenetic" technique that uses two special types of ion channels, halorhodopsin and channelrhodopsin, that are activated by light. By employing viral injection techniques, we will express these light-activated channels selectively in prefrontal cortical neurons and their projections, which terminate in the nucleus accumbens. We can then use laser light with specific wavelengths to either excite (with channelrhodopsin) or inhibit (with halorhodopsin) only those presynaptic terminals arriving from the prefrontal cortex in accumbens, allowing unprecedented spatial selectivity. We predict that yellow light, which activates halorhodopsin, will inhibit the firing of glutamate-releasing cortical neurons and thus promote food intake in normal, sated animals. We believe that this is similar to what is occurring in obese, habitually eating individuals- a reduction in firing of the prefrontal cortical neurons. The second half of the proposal seeks to reverse this aberrant behavior. We will first demonstrate that overnutrition, as a result of a high-fat diet, induces habit-like responses to food intake. We will then reverse this habit behavior by using blue light, which will activate the prefrontal cortical neurons via the channelrhodopsin and restore glutamate to the accumbens. By resolving this important connection between these brain areas, we hope to provide new insights into the treatment of obesity and related disorders. PUBLIC HEALTH RELEVANCE: This research attempts to better understand how obesity may alter decision making to reinforce detrimental eating habits. By determining how this occurs in the brain, we will be better able to provide therapeutic interventions that may help control weight gain and diseases associated with obesity.